Structure-guided Design and Immunological Characterization of Immunogens Presenting the HIV-1 gp120 V3 Loop on a CTB Scaffold
Department of Medicine
AIDS Vaccines; Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; *Cholera Toxin; Drug Design; HIV Antibodies; *HIV Envelope Protein gp120; HIV-1; Immunization; *Peptide Fragments; Rabbits
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences | Virology
V3 loop is a major neutralizing determinant of the HIV-1 gp120. Using 3D structures of cholera toxin B subunit (CTB), complete V3 in the gp120 context, and V3 bound to a monoclonal antibody (mAb), we designed two V3-scaffold immunogen constructs (V3-CTB). The full-length V3-CTB presenting the complete V3 in a structural context mimicking gp120 was recognized by the large majority of our panel of 24 mAbs. The short V3-CTB presenting a V3 fragment in the conformation observed in the complex with the 447-52D Fab, exhibited high-affinity binding to this mAb. The immunogens were evaluated in rabbits using DNA-prime/protein-boost protocol. Boosting with the full-length V3-CTB induced high anti-V3 titers in sera that potently neutralize multiple HIV virus strains. The short V3-CTB was ineffective. The results suggest that very narrow antigenic profile of an immunogen is associated with poor Ab response. An immunogen with broader antigenic activity elicits robust Ab response.
DOI of Published Version
Virology. 2010 Sep 30;405(2):513-23. Epub 2010 Jul 21. Link to article on publisher's site
Totrov, Maxim; Jiang, Xunqing; Kong, Xiang-Peng; cohen, Sandra; Krachmarov, Chavdar; Williams, Constance; Seaman, Michael S.; Cardozo, Timothy; Gorny, Miroslaw K.; Wang, Shixia; Lu, Shan; Pinter, Abraham; and Zolla-Pazner, Susan, "Structure-guided Design and Immunological Characterization of Immunogens Presenting the HIV-1 gp120 V3 Loop on a CTB Scaffold" (2010). Open Access Articles. 2292.